Implantable system for delivery of fluid-sensitive agents to animals

ABSTRACT

A delivery system (10) is disclosed for delivering a fluid-sensitive beneficial agent (7) such as a somatotropin, or an analogue or derivative thereof, to an animal such as a bovine. The delivery system comprises a wall that surrounds an internal compartment, said wall comprising a first wall section that limits the passage of fluid into the system and a second wall section that permits the passage of fluid into the system. An exit passageway is provided for delivering the beneficial agent an interior compartment (18) to the animal. The exit passageway is sealed with a wax seal (30) which is expelled through the passageway (13) as the internal pressure within the device (10) reaches a predetermined &#34;bursting&#34; pressure. The passageway (13) is preferably sized to compensate for slight variations in the efflux of the beneficial agent and to maintaining a sufficient volumetric outflow rate of beneficial agent in order to minimize influx of biological fluids from the external environment back into the device once the seal (30) is expelled.

TECHNICAL FIELD

This invention relates to a beneficial agent (eg, a drug) deliverysystem, such as an implantable osmotically driven delivery system, andmore particularly, the invention relates to a device that protects andadministers a fluid-sensitive beneficial agent to a fluid environment ofuse.

BACKGROUND ART

Delivery devices for administering a beneficial agent to a biological,fluid environment of use are known to the prior art. See, for example,U.S. Pat. Nos. 5,137,727; 5,174,999; and 5,238,687.

These devices comprise a housing including fluid-impermeable first wallsection and a fluid permeable second wall section. A beneficial agent isenclosed within the first wall section. An expandable driving member isenclosed within the second wall section. A slidable piston separates thebeneficial agent from the expandable driving member. An exit passagewayis formed in the fluid impermeable wall section. As fluid is imbibedthrough the semipermeable wall section, the driving member expandswithin the housing, pushing the slidable piston which forces thebeneficial agent through the exit passageway.

The delivery devices described in the above patents operate successfullyfor their intended use and they can deliver many beneficial agents fortheir intended effects. Now, it has been observed that their use can belimited because difficulties associated with these delivery deviceswhich include beneficial agents that are sensitive to biological fluidsand to fluids containing biological gases; uneven delivery of thosebeneficial agents from the device and difficulties associated withshortening the start-up time for delivering the beneficial agents fromthe device.

Implanted devices are continually exposed to biological fluids naturallypresent in the body. Many beneficial agents, including proteins,peptides, and hormones, may be degraded (e.g., hydrolyzed) or diluted byfluids that enter the implanted device during operation thereof. Thefluids may contact the agents by entering through the exit passageway,through the wall joints, or around the slidable piston. In addition, thedelivery of beneficial agents from these devices may be uneven. Bubblesmay impede passage of the agents through the exit passageways. Pressuremay be created by differential expansion between the agent formulationand the materials used to construct the device altering the actual agentdelivery rate. Furthermore, the disclosed devices may be unable toprovide the desired delivery rates and start-up times.

Thus, there is a need for a delivery system for administering a drug orother beneficial agent that is sensitive to aqueous biological fluids ata controlled rate and for protecting the beneficial agent, and whichdelivery device possesses the ability to continually deliver theprotected beneficial agent in effective amounts, over the desired time,particularly in the fields of human and veterinary medicine (eg, in thebreeding and management of farm animals).

DISCLOSURE OF THE INVENTION

The present invention is directed to a fluid-imbibing delivery device ordispenser for storing and protecting a fluid-sensitive beneficial agentand for dispensing the beneficial agent to a fluid environment of useover a prolonged period of time. Protecting the beneficial agent reducesthe evaporation of fluid from a beneficial agent solution and/or thedilution or degradation of the beneficial agent by the influx of fluidfrom the environment of use, thereby maintaining its efficacy.

In accordance with one aspect of the present invention, the deliverydevice is provided with a sealed exit passageway to protect thebeneficial agent from the ingress of biological fluid from theenvironment of use. The sealed passageway opens once a predeterminedinternal pressure has been achieved after placing the delivery device inthe environment of use. Once the exit passageway has been opened, theagent in the device is isolated from the biological fluid diffusing inthrough the exit passageway by means of outflow of the beneficial agentat a sufficient rate to prevent the influx of biological fluid from theenvironment of use. This is achieved by providing sufficient volumetricefflux of the beneficial agent formulation which is pumped into theevironment of use. The volumetric flow of the beneficial agentformulation from the device is a function of the internal osmoticpressure generated by the expandable osmotic driver and by the size (ie,cross-sectional area) of the exit passageway. In addition, thepassageway preferably has an extended length which is sufficient toprevent biological fluids in the environment of use from diffusing intothe compartment enclosing the beneficial agent when the efflux istemporarily halted, e.g., when the partition movement is impeded.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawing figures, which are not drawn to scale, and wherein likereference numerals refer to like elements, are set forth to illustratevarious embodiments of the invention as follows:

FIG. 1 is a cross-sectional view of one embodiment of the deliverydevice of the invention, illustrating one structural embodiment of thedelivery system comprising a first walled section and a second walledsection.

FIG. 2 is an enlarged fragmented cross-sectional view of the mating endcap of FIG. 1.

FIG. 3 is a graph showing the time (hours) needed to burst a wax seal ofthe type shown in FIGS. 1 and 2 at various internal pressures.

FIG. 4 is a graph showing the effect of exit passageway diameter onwater ingress, measured as percent dilution of a beneficial agentformulation.

FIG. 5 is a graph of internal bursting pressure versus wax sealthickness for a preferred wax seal in accordance with the presentinvention.

FIG. 6 is a graph of internal bursting pressure for various mixed waxseals in accordance with the present invention.

MODES FOR CARRYING OUT THE INVENTION

FIG. 1 illustrates one embodiment of the delivery device according tothe present invention. Delivery system 10 of FIG. 1 comprises a housing11 formed of a wall 12, which wall comprises a first wall section 12aand a second wall section 12b. Wall 12 encloses and defines an internalcompartment 18. Delivery system 10 has at least one exit passageway 13for delivering a beneficial agent formulation 7 from delivery system 10,the inlet of which is in continuous contact with the beneficial agentduring storage and use. In accordance with the present invention, theexit passageway 13 is initially sealed with a wax seal 30, discussedbelow, a portion of which is discharged out through passageway 13 whenthe pressure within compartment 18 rises above a predetermined burstingpressure during operation of device 10.

Wall section 12a may be in the form of a tubular member having a firstand a second open ends 32 and 34, respectively. In this particularembodiment, an end cap 36 is positioned on first wall section 12a at itslead end 9.

The device 10 isolates the beneficial agent from exposure to environmentfluids diffusing into the compartment 18 defined by the first wallsection 12a. First wall section 12a encloses and defines the internalspace of compartment 18 initially occupied by the beneficial agent 7.First wall section 12a also comprises a composition that issubstantially impermeable to the exchange of fluid, beneficial agent 7and other ingredients contained in delivery system 10. The phrasesubstantially impermeable, as used herein, indicates the volume ofexternal fluid passing through the first wall section 12a issubstantially negligible, that is, about zero up to about 1μ or up toabout 1 mL/day. As a result, wall section 12a serves as a means forsubstantially protecting a beneficial agent 7 that is sensitive toexterior fluid present in the environment of use. Other representativecompositions for forming first section 12a such as vinylidene chloridecopolymers and terpolymers, acrylonitrile polymers, halogenated polymersand polycarbonates are discussed in U.S. Pat. No. 5,057,318,incorporated by reference herein.

Wall section 12b surrounds that portion of internal compartment area 18that contains expanding means 25 for expanding and for occupying spacein compartment 18 for delivery of a beneficial agent formulation fromdelivery system 10. Wall section 12b has an open end 40 and an enclosedend 42, the enclosed end at end 8 and the open end distal therefrom.Second wall section 12b is permeable to the passage of fluid and it issubstantially impermeable to the passage of other ingredients containedin delivery system 10. The thickness and the surface area of the secondwall section 12b contribute to the rate of passage of fluid through themembrane second wall section. The rate of passage is a function ofthickness, the surface area, the particular compound used in forming themembrane cup and the particular expandable driving means. Thus, adesired fluid flow rate of fluid from the environment of use into thedelivery device of about 10-15 μgm H₂ 0/day and more particularly about12-14 μgm H₂ 0/day can be achieved by manipulation of the abovedescribed factors.

Typical semipermeable materials, flux enhancers and plasticizers forforming wall 12b are known in the art, and are described in detail inU.S. Pat. No. 5,057,318.

Referring again to FIG. 1, compartment 18 comprises a beneficial agentformulation 7, which beneficial agent formulation 7 comprises abeneficial agent 7a, identified by dots, and a pharmaceuticallyacceptable carder 21, identified by wavy lines. The pharmaceuticallyacceptable carder may include more than one ingredient, such as a buffer22, identified by horizontal dashes; a pharmaceutically acceptablevehicle 23, identified by vertical lines; a pharmaceutically acceptablesurfactant 24, identified by slanted lines; and other formulationingredients, as are known in the art. Delivery device 10 in itscompartment 18 can also comprise pharmaceutical carder 21. Carder 21 mayoptionally include viscosity modulating vehicles (23), buffers (22),surfactants (24), dyes, and other additives known in the art, examplesof which are disclosed in U.S. Pat. Nos. 5,034,229 and 5,135,123 tocomprise the beneficial agent formulation 7.

One class of fluid-sensitive agents that are presently preferred fordelivery from the devices of the present invention are growth factors,including bovine somatotropin and analogues and derivatives thereof. Thedevices of the present invention provide a means for delivering aneffective amount of a beneficial agent for causing increasedproductivity, such as, in the case of the somatotropins, a higher feedconversion efficiency, improved carcass quality, higher than normal rateof animal weight gain, and increased milk production. Most preferablythe bovine somatotropin is present in an amount of about 25 to 60 wt %of the beneficial agent formulation 7, preferably about 30 to 45 wt %.

Wall section 12b surrounds, an expanding means 25 optionally comprisingmembers 25a-f. Expanding means 25 expands in response to fluid imbibedacross wall 12b and optionally comprises an osmagent homogeneously orheterogeneously blended with binder.

The expandable driving means 25, initially surrounded by second wallsection 12b and operable for pushing the beneficial agent formulation 20from delivery device 10 comprises, in a presently preferred embodiment,an osmopolymer. The expandable driving means 25 in another preferredembodiment comprises an osmagent. The expandable driving means 25 yet inanother preferred embodiment comprises an optional osmagent dispersedwithin the osmopolymer. Osmagents and osmopolymers are known to the artin U.S. Pat. Nos. 3,865,108; 4,002,173; 4,207,893; 4,327,725; 4,612,008;5,034,229 and 5,135,123 for example, the disclosures of which areincorporated by reference herein.

In a presently preferred embodiment, delivery device 10 comprises aplurality of expandable driving means 25a-f initially housed in secondwall section 12b. This configuration is merely illustrative and theremay be any number of driving means present. Generally, there are fromone to six expandable driving means; however, this number is notcontrolling. The expandable driving members in a presently preferredembodiment are formed as depots or layers and comprise like or unlikecompositions. For example, driving means 25a-f can be made as tabletscomprising like osmopolymers or like osmagents, or they can compriseunlike osmopolymers or unlike osmagents, or one or more of the memberscan be a composition comprising an osmopolymer together with anosmagent.

Formed on the outer surface 52 of the wall section 12b is the secondsmoothing shoulder 46. Second smoothing shoulder 46 is positioned toco-extend with the second open end 34 of the first wall section 12a whenthe second wall section is telescoping received within the first wallsection. External discontinuities or surface fiction of the implantdevice are this minimized and provide a smooth transition between thefirst and second wall sections. In this particular embodiment, theportion of the second wall section 12b inserted within the first wallsection 12a has the same thickness as that portion outside the firstwall section. In addition, as a result of this construction, the insidesurface of the first and second wall sections facilitates the travel ofthe piston along the formed smooth continuous interior surface.

In addition, end cap 35, best illustrated in FIG. 2, provides a meansfor simply and conveniently assembling the device of the invention, andparticularly for filling the device with internal components such as theosmotic driver, the partition and the beneficial agent formulation. Theend cap 38 is substantially impermeable to fluid, providing protectionfor the fluid-sensitive beneficial agent. Materials for forming end cap38 may be chosen from those materials useful in preparing impermeablefirst wall section 12a. The end cap 38 is specifically beneficial whendelivering fluid sensitive materials and protects the material to bedelivered before and after activation of the device.

End cap 38 includes an exterior cap side 70, an interior end cap side 72and an exit passageway 13 extending from the external environment 41into internal chamber 18 containing formulation 7. The endcap 35isolates the beneficial agent by providing an adequate formulation flowrate, driven by fluid swellable driving means 25 and a partition member27 including piston 29, to prevent dilution of the formulation inchamber 18 by the inflow of fluids from the external environment 41. Theexit passageway 13 is sized in diameter and length to provide asufficient beneficial agent formulation efflux which any biologicalfluid present in the external environment to flow through passageway 13and into the interior of device 10.

The diameter of the exit passageway 13 determines the volumetric outwardflow of the beneficial agent 7 from the internal compartment 18. Thelength of the exit passageway 13 provides a means for compensating forslight variations in the efflux of the beneficial agent. A passagewaydiameter of about 0.25 to 0.55 mm, preferably about 0.4 mm, is generallysufficient to generate a sufficient outward volumetric flow of thebeneficial agent. A passageway length of about 1.5 to 3.5 mm, preferablyabout 2.5 mm, is sufficient to compensate for slight variations in theefflux of the beneficial agent.

The terms "exit means" and "exit passageway", as used herein, comprisemeans and methods suitable for the metered release of the beneficialagent 7 from compartment 18 of delivery device 10. This includesmaintaining sufficient efflux or outward volumetric flow of thebeneficial agent to prevent an inward flow of biological fluid from theexternal environment and prevent contact with the beneficial agentformulation in the compartment 18. The exit passageway includes at leastone passageway, orifice, or the like, through first wall section 12a orthe end cap 38 for establishing fluid communication between compartment18 and the external environment of use 41. The passageway 13 can haveany cross-sectional shape such as round, triangular, square, elliptical,and the like, but preferably is roughly circular, for assisting in themetered release of beneficial agent from delivery device 10. Deliverydevice 10 can be constructed with multiple passageways 13 inspaced-apart relation. Passageways and materials, equipment and methodsfor forming passageways are disclosed in U.S. Pat. No. 5,034,229.

Seal 30 blocks the exit passageway 13 until a pre-determined burstingpressure is reached within the device. A recess 37 is preferablyprovided in end cap 30 so that the wax 30 can be placed therein while ina molten state. Using this procedure, the wax seal 30 will generallyfill substantially the entire volume of the exit passageway 13. Theinternal seal 30 provides point of use readiness without having toreopen the device, such as with a break-off tab, provides for a longterm stability seal, protects formulation at start-up and has aconsistent rupture pressure to provide consistent start-up. In addition,since the exit passageway 13 is occluded until the pre-determinedpressure is reached, the beneficial agent is isolated within theinternal compartment 18. Furthermore, when the pressure is sufficient toexpel the plug of wax within passageway 13, the osmotic energy sourceprovides sufficient pressure against piston 29 to ensure continuouspumping of the beneficial agent formulation once the plug seal has beenburst.

This seal 30 serves several purposes. First, seal 30 seals exitpassageway 13 to prevent premature delivery of a beneficial agent 7 fromdelivery device 10 and to prevent evaporation of volatile cardercomponents such as water or other solvents during storage. By sealingpassageway 13, seal 30 helps maintain the clean or optionally sterileenvironment inside delivery device 10, thereby protecting the materialsinside the delivery device from oxidation and also protects thebeneficial agent formulation from dilution by body fluids followingimplantation. The release of the seal 30 occurs when the pressuregenerated within the device is greater than the burst pressure of theseal. Those skilled in the ad will recognize this must necessarilyexceed the pressure outside the device in the environment of use.

In one embodiment, the seal 30 is comprised of a wax. Mineral,vegetable, plant, animal, petroleum and synthetic waxes may be used.Preferably, the wax is a synthetic or refined wax, as opposed to anatural source wax (eg, beeswax), as these are more consistant incomposition and physical propedies. More preferably, the wax is amicrocrystalline petroleum wax. Preferred waxes are said by Witco ofGreenwich, Conn. under the tradnames Multiwax X145a and 180-M. Mostpreferred is a mix of these two grades of wax. Using these waxesconsistent bursting pressures for the seal 30 in end cap 38 have beenachieved. Although the invention is not limited to any particular rangeof bursting pressure, using wax based seals, bursting pressures of about0.4 to 0.7 kg/cm² (gauge) are typical.

When wax is utilized as the material of seal 30, the bursting pressureof the seal 30 can easily be modified by varying the thickness of theseal or the hardness of the wax. The thickness can be altered by varyingthe depth of the recess 37 or the amount of wax in recess 37. Thehardness of the wax can be modified by varying the percent compositionof a combination of hard and soft microcrystalline waxes as shown inFIGS. 5 and 6. Other waxes which can be used to form seal 30 includemontan wax, ozokerite wax, carnuba wax, myricyl cerotate wax, beeswax,parafin wax, spermaceti, ceresine, gamma wax, Japan wax, ouricury,ceresin wax and castor wax.

There are limitations on the maximum strength of the seal 30 determinedby the amount of pressure the expandable driving member can generate atstart-up without exceeding the yield strength of the secondsemipermeable wall section 12B. If the force to expel the seal 30exceeds this yield strength then failure at the joint between the wallportions 12a and 12b can occur, which can result in system failure.

Delivery device 10 can be implanted into the peritoneal cavity of ananimal (eg, a human) using a conventional implanting apparatus.Generally, an implanter comprises a tubular member with a centrallongitudinal axial bore, a pointed, elongated, annular concavely beveledimplanting end and an implant-charging end. The implanting end and thecharging end communicate through a bore. A plunger adapted to beremovably inserted in the bore is designed for slidable movement thereinfor applying the necessary force for implanting the implant.Alternatively, the implant can be surgically or subcutaneously implantedin the peritoneal cavity.

Delivery device 10 can be manufactured by standard manufacturingtechniques. In one process, the first wall section 12a and the secondwall section 12b are independently injection molded or extruded into thedesired shape. Then, the first wall section 12a is filled with thebeneficial agent composition. The second wall section 12b is filled withan expandable driving member or members, and the piston 29 is next addedthereto in layered arrangement. Optionally, the piston 29 may be addedto the first wall section 12a after filling the wall section withbeneficial agent, in addition to, or instead of, the partition layeradded to second wall section 12b. Next, the two sections at their openends are slid together.

The delivery device of the present invention can be manufactured fordelivering numerous beneficial agents, including drugs, at a controlledrate to a presently preferred biological environment of use such aswarm-blooded animals, including humans; ruminants, such as bovines andsheep; porcines, such as hogs and swine; horses; and the like. Thedelivery devices provide for high loading of a beneficial agent and forits improved delivery in beneficially effective amounts (that is,amounts that provide a beneficial effect) over time. It is to beunderstood that the delivery devices can take a wide variety of shapes,sizes and forms adapted for delivering beneficial agents to environmentsof use. For example, the devices manufactured as delivery devices can beused for dispensing a beneficial agent in the anal-rectal passageway, inthe cervical canal, as an artificial gland, in the vagina, as asubcutaneous or intraperitoneal implant, and the like. The deliverydevices can be used in hospitals, nursing homes, outpatient clinics,sickrooms, veterinary clinics, farms, zoos, and other environments ofuse.

EXAMPLE 1

FIG. 5 is a graph depicting the internal bursting pressure for a "mixed"wax seals comprising 50% Multiwax 180-M and 50% Multiwax X-145a, theseals having thicknesses between 1.3 and 2.5 mm, from exit passagewayshaving a diameter of 0.4 mm and a length of 2.54 mm. The burstingpressure for those seals having a thickness of 1.3 mm was consistentlyabout 1.6 kg/cm².

Thus, an exit passage having a 0.4 mm diameter and a length of 2.5 mm,in fluid contact or abutted by a seal of 1.3 mm thick, bursts the sealat about 1.6 kg/cm² (gauge).

EXAMPLE 2

FIG. 3 is a graph showing the effect of the exit passageway diameter onthe diffusion of water using an exit passageway length of 2.5 mm andspecified diameter. Empirical observations of the respective devicesindicate that the beneficial agent formulation turned white in alldevices with 1.3 mm diameter passageways with small pockets of waterentrained in the formulation. The beneficial agent formulation was clearin all devices having an exit passageway diameter of about 0.4 mm.

Thus an exit aperture having a diameter of 0.4 mm provides sufficientoutward volumetric flow or efflux of the beneficial agent from thecompartment 18 to substantially prevent diffusion of external fluid backinto the compartment 18.

The novel devices of this invention use means for the obtainment ofprecise release rates in a fluid environment of use while simultaneouslymaintaining the integrity of the device and the stability of thefluid-sensitive beneficial agent 7 within the device. While there hasbeen described and pointed out features of the invention as applied topresently preferred embodiments, those skilled in the art willappreciate that various modifications, changes, additions and omissionsin the devices illustrated and described can be made without departingfrom the spirit of the invention.

It is claimed:
 1. A device for delivering a beneficial agent to a fluid environment of use, the device comprising:a) a housing comprising a fluid impermeable wall section, the housing containing the beneficial agent; b) an exit passageway for fluidly connecting the housing interior to the environment of use; c) an energy source for increasing pressure within the housing when the device is in the environment of use; d) a sealing material, adjacent the exit passageway, the material being effective to seal the exit passageway before the housing is pressurized, at least a portion of the material being expelled through the passageway after the housing is pressurized, thereby opening the exit passageway, thereafter allowing continuous release of a therapeutically effective amount of beneficial agent during the entire time of delivery.
 2. The device of claim 1, wherein the energy source comprises an osmotic driver.
 3. The device of claim 1, wherein the sealing material comprises a wax.
 4. The device of claim 3, wherein the wax is a microcrystalline petroleum wax.
 5. The device of claim 3, wherein the wax is a blend of a plurality of different waxes.
 6. The device of claim 5, wherein the different waxes have differing hardnesses.
 7. The device of claim 1, wherein the sealing material maintains the exit passageway sealed until the pressure generated by the energy source exceeds a predetermined pressure.
 8. The device of claim 7, wherein the predetermined pressure is between about 0.4 and 0.7 kg/cm².
 9. The device of claim 1, wherein the exit passageway has a diameter of about 0.25 to 0.55 mm.
 10. The device of claim 1, wherein the exit passageway has a length of about 1.5 to 3.5 mm.
 11. A method of making a device according to claim 1, comprising:sealing the exit passageway with a material which is expelled through the passageway when the housing is pressurized to a predetermined pressure level in order to open the exit passageway thereafter allowing continuous release of a therapeutically effective amount of beneficial agent during the entire time of delivery.
 12. The method of claim 11, including increasing pressure within the housing by means of an osmotic driver.
 13. The method of claim 11, wherein the sealing material comprises a wax.
 14. The method of claim 13, wherein the wax is a microcrystalline petroleum wax.
 15. The method of claim 13, wherein the wax is a blend of a plurality of different waxes.
 16. The method of claim 15, wherein the different waxes have differing hardnesses.
 17. The method of claim 11, including maintaining the exit passageway sealed until the pressure generated by the energy source exceeds a predetermined pressure.
 18. The method of claim 17, wherein the predetermined pressure is between about 0.4 and 0.7 kg/cm².
 19. The method of claim 11, wherein the exit passageway has a diameter of about 0.25 to 0.55 mm.
 20. The method of claim 11, wherein the exit passageway has a length of about 1.5 to 3.5 mm. 